Progressive plasticity during colorectal cancer metastasis

Nature, Год журнала: 2024, Номер unknown

Опубликована: Окт. 30, 2024

As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, acquire resistance successive and eventually cause death1,2. Mutations largely conserved between metastatic from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression therapy resistance3–5. However, we lack an understanding of cell states mechanisms by which transition. Here, cohort biospecimen trios same-patient normal colon, colorectal cancer, show that, although adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose identities reprogram into highly fetal progenitor state before undergoing non-canonical differentiation divergent squamous neuroendocrine-like process is exacerbated metastasis chemotherapy associated with poor patient survival. Using matched patient-derived organoids, demonstrate exhibit greater cell-autonomous multilineage potential response microenvironment cues compared their lineage-restricted tumour counterparts. We identify PROX1 as repressor non-intestinal lineage state, downregulation licenses reprogramming. Colorectal involves dramatic loss PROX1-mediated repression lineages.

Язык: Английский

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Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells

Cancer Discovery, Год журнала: 2024, Номер 14(5), С. 866 - 889

Опубликована: Март 26, 2024

Abstract Patients with estrogen receptor–positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late longitudinally profiled a rare cohort treated long-term neoadjuvant ETs until progression. Next, developed an in vitro evolutionary study record the adaptive strategies individual lineages unperturbed parallel experiments. Our data demonstrate induce nongenetic cell state transitions into dormancy stochastic subset cells via epigenetic reprogramming. Single divergent phenotypes awaken unpredictably absence recurrent alterations. Targeting dormant epigenome shows promising activity against adapting cells. Overall, this uncovers contribution adaptation evolution resistance ETs. Significance: This advances understanding therapy-induced potential clinical implications for cancer. Estrogen receptor-positive adapt treatment entering characterized strong heterochromatinization no changes. rewiring impairs See related commentary Llinas-Bertran et al., p. 704. article is featured Selected Articles from Issue, 695

Язык: Английский

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Decoding the interplay between genetic and non-genetic drivers of metastasis

Nature, Год журнала: 2024, Номер 629(8012), С. 543 - 554

Опубликована: Май 15, 2024

Язык: Английский

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The evolutionary theory of cancer: challenges and potential solutions

Nature reviews. Cancer, Год журнала: 2024, Номер 24(10), С. 718 - 733

Опубликована: Сен. 10, 2024

Язык: Английский

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The Epigenetic Hallmarks of Cancer

Cancer Discovery, Год журнала: 2024, Номер 14(10), С. 1783 - 1809

Опубликована: Окт. 4, 2024

Abstract Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, latest iteration of cancer hallmarks, “nonmutational epigenetic reprogramming” was newly added. However, epigenetics, much like genetics, broad scientific area that deserves further attention due its multiple roles initiation, progression, adaptive nature. Herein, we present detailed examination hallmarks affected human cancer, elucidating genes involved, dissecting disrupted landscapes for DNA methylation, histone modifications, chromatin architecture define disease. Significance: characterized by constant evolution, spanning from initial premalignant stages advanced invasive disseminated stages. It pathology able adapt survive amidst hostile microenvironments diverse treatments implemented medical professionals. The more fixed setup genetic structure cannot fully provide transformed cells with tools but rapid plastic nature changes ready task. This review summarizes ecological success our bodies.

Язык: Английский

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Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal

Cancer Discovery, Год журнала: 2025, Номер unknown, С. OF1 - OF23

Опубликована: Янв. 8, 2025

Abstract Although the key aspects of genetic evolution and their clinical implications in clear-cell renal cell carcinoma (ccRCC) are well documented, how features coevolve with phenotype tumor microenvironment (TME) remains elusive. Here, through joint genomic–transcriptomic analysis 243 samples from 79 patients recruited to TRACERx Renal study, we identify pervasive nongenetic intratumor heterogeneity, over 40% not attributable alterations. By integrating transcriptomes phylogenetic structures, observe convergent specific phenotypic traits, including proliferation, metabolic reprogramming, overexpression putative cGAS–STING repressors amid high aneuploidy. We also uncover a coevolution between T-cell repertoire, as longitudinal shift TME an antitumor immunosuppressive state, linked acquisition recurrently late ccRCC drivers 9p loss SETD2 mutations. Our study reveals clinically relevant hitherto underappreciated patterns ccRCC. Significance: Using samples, reveal recurrent exclusively governed by factors, depletion, receptor coevolution, potential repression, increased proliferation. These can aid management guide novel treatment approaches.

Язык: Английский

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Punctuational evolution is pervasive in distal site metastatic colonization

Proceedings of the Royal Society B Biological Sciences, Год журнала: 2025, Номер 292(2039)

Опубликована: Янв. 1, 2025

The evolution of metastasis, the spread cancer to distal sites within body, represents a lethal stage progression. Yet, evolutionary dynamics that shape emergence metastatic disease remain unresolved. Here, using single-cell lineage tracing data in combination with phylogenetic statistical methods, we show trajectory is littered bursts rapid molecular change as new cellular subpopulations appear, pattern known punctuational evolution. Next, by measuring across cascade, effects are concentrated formation secondary tumours at sites, suggesting qualitatively different modes may drive primary and tumour Taken whole, our findings provide empirical evidence for distinct patterns early late stages approach provides framework study metastasis more nuanced level than has been previously possible.

Язык: Английский

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Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications

Cancers, Год журнала: 2023, Номер 15(16), С. 4020 - 4020

Опубликована: Авг. 8, 2023

Colorectal cancer (CRC) is a global health concern and leading cause of death worldwide. The disease’s course response to treatment are significantly influenced by its heterogeneity, both within single lesion between primary metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, BRAF, provide valuable guidance for decisions patients with CRC. While high concordance exists mutational status lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable identifying genetic predicting prognosis RAS-mutated CRC patients. Tumor can arise from non-genetic factors, affecting development therapy. To comprehend address clonal evolution intratumoral comprehensive genomic studies employing techniques next-generation sequencing computational essential. Liquid biopsy, notably through ctDNA, enables real-time monitoring. However, challenges remain standardizing procedures accurately characterizing subpopulations. Various models elucidate the origin highlighting intricate molecular pathways involved. This review focuses on intrapatient CRC, an emphasis clinical applications.

Язык: Английский

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From Retrograde Menstruation to Endometrial Determinism and a Brave New World of “Root Treatment” of Endometriosis: Destiny or a Fanciful Utopia?

Biomolecules, Год журнала: 2023, Номер 13(2), С. 336 - 336

Опубликована: Фев. 9, 2023

Practically unknown outside of China, the "endometrial determinism" theory was proposed to account for apparent gap between relatively low prevalence endometriosis and nearly universal retrograde menstruation. Attracting uncritical advocacy, culminates in a recent consensus by elite Chinese gynecologists favor "root treatment", intended nip bud. Correcting endometrial "defects" can gain further momentum presence cancer-driver mutations such as KRAS endometrium women with introduction therapeutics aiming rectify effect these cancer treatment. We provide critical appraisal evidence aberrations relevant experimental evidence. All available "defect" is invariably post hoc may well be secondary induced endometriosis. propose that needs demonstrate clear causal phylogenetic relationship argue while it highly likely consequence menstruation, case molecular sole or necessary determinant remains proven. "Root treatment" worthy ambition but now close fanciful Utopia.

Язык: Английский

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Cancer phylogenetic tree inference at scale from 1000s of single cell genomes

Peer Community Journal, Год журнала: 2023, Номер 3

Опубликована: Июль 21, 2023

A new generation of scalable single cell whole genome sequencing (scWGS) methods allows unprecedented high resolution measurement the evolutionary dynamics cancer populations. Phylogenetic reconstruction is central to identifying sub-populations and distinguishing mutational processes that gave rise them. Existing phylogenetic tree building models do not scale tens thousands genomes achievable with current scWGS methods. We constructed a model associated Bayesian inference procedure, sitka, specifically for data. The method based on novel encoding copy number (CN) data, sitka transformation, simplifies site dependencies induced by rearrangements while still forming sound foundation inference. transformation us design Markov chain Monte Carlo (MCMC) algorithms. Moreover, we introduce point mutation calling incorporates CN data underlying overcome low per-cell coverage scWGS. demonstrate our three datasets, including PDX series, analyse topological properties inferred trees. Sitka freely available at https://github.com/UBC-Stat-ML/sitkatree.git

Язык: Английский

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